Combining hu14.18-IL2 and NK cell infusions to treat neuroblastoma

神经母细胞瘤是儿童最常见的颅外实体瘤，表达 其表面有二唾液酸神经节苷脂GD2。适用于患有高危疾病或以下疾病复发的患者 在完成治疗的过程中，选择有限。异基因造血干细胞移植是一种 将健康捐献者的造血干细胞输注给接受高剂量治疗的患者 用于化疗和/或放射治疗，临床上通常用于白血病或淋巴瘤儿童。但 到目前为止，异基因造血干细胞移植在利用移植物抗肿瘤(GVT)效应攻击神经母细胞瘤方面取得的成功有限， 并引入了致命性移植物抗宿主病(GVHD)。这项建议的长期目标是 增强GVT抗神经母细胞瘤的作用。这项建议探讨了改善GVT效果的3个具体目标 采用异基因造血干细胞移植的动物模型。首先，我们将探索一种名为hu14.18-IL2的免疫细胞因子的用途。 人源化GD2单抗与白介素2连接，增强GVT效应，改善 移植的效果。这种抗体已经在临床试验中用于神经母细胞瘤的儿童。 但不是治愈的，而且还没有在allallHSCT环境中进行测试。第二，我们将激活异体自然 NK细胞与表达IL-15和CD137L的人工抗原提呈细胞，并将它们输注用于 首次将hu14.18-IL2作为进一步改善GVT的联合策略。我们会控制任何潜在的可能性 GVHD通过抑制JAK/STAT通路和阻断肿瘤坏死因子-α的产生来实现。最后，我们将 用一种非放射性的氟同位素(⁹F)标记NK细胞，使这些细胞可以通过核磁共振检测到， 确定⁹F标记的NK细胞在异基因造血干细胞移植后如何转运到神经母细胞瘤肿瘤，以及hu14.18-IL2是否可以 进一步吸引NK细胞进入肿瘤。最终目标是支持国家科学基金的研究优先事项 癌症研究所通过开发将导致神经母细胞瘤的新疗法的研究。任何一项的成功 个体化的目标将是使异基因造血干细胞移植对神经母细胞瘤更有效的重大进展。成功 整个提案的翻译将带来一个创新的联合免疫治疗平台 神经母细胞瘤。

Neuroblastoma is the most common extracranial solid tumor seen in children, and expresses the disialoganglioside GD2 on its surface. For patients who have high risk disease or whose disease recurs after completing therapy, there are limited options. Allogeneic hematopoietic stem cell transplant (AlloHSCT) is a transfusion of hematopoietic stem cells from a healthy donor to a patient who has been treated with high doses of chemotherapy and/or radiation, and is typically used clinically for children with leukemia or lymphoma. But alloHSCT has had limited success thus far in attacking neuroblastoma with a graft-versus-tumor (GVT) effect, and has introduced lethal graft-versus-host-disease (GVHD). The long term objective of this proposal is to enhance the GVT effect against neuroblastoma. This proposal explores 3 specific aims to improve GVT effects using animal models of alloHSCT. First we will explore usage of an immunocytokine called hu14.18-IL2, a humanized GD2 monoclonal antibody linked to interleukin (IL)-2, to enhance the GVT effect, improving the efficacy of the transplant. This antibody has already been given to children with neuroblastoma in clinical trials but is not curative, and has not been tested in the alloHSCT setting. Second, we will activate allogeneic natural killer (NK) cells with IL-15 and CD137L-expressing artificial antigen presenting cells, and infuse them for the first time with hu14.18-IL2 as a combination strategy for improving GVT further. We will control any potential GVHD by inhibiting the JAK/STAT pathway and blocking tumor necrosis factor-alpha production. Lastly, we will label NK cells with a nonradioactive isotope of fluorine (¹⁹F) that will make these cells detectable by MRI, determine how ¹⁹F-labeled NK cells traffic to neuroblastoma tumors after alloHSCT and if hu14.18-IL2 can further attract NK cells to the tumor. The ultimate goal is to support the research priorities of the National Cancer Institute by developing research that will lead to novel therapies for neuroblastoma. Success of any of the individual aims will be a major advance in making alloHSCT more effective for neuroblastoma. Successful translation of the entire proposal will lead to an innovative combination immunotherapy platform for treating neuroblastoma.